Amyloid light-chain (AL) amyloidosis is an ultra-rare disease associated with significant morbidity and mortality. Few studies have examined the global epidemiology of this condition. This study ...estimated the diagnosed incidence and 1-year, 5-year, 10-year, and 20-year period prevalence of AL amyloidosis in 2018 for countries in and near Europe, and in the United States (US), Canada, Brazil, Japan, South Korea, Taiwan, and Russia. A systematic literature review (SLR) was conducted to identify country-specific, age- and gender-specific diagnosed incidence of AL amyloidosis and observed survival data-point inputs for an incidence-to-prevalence model. Extrapolations were used to estimate incidence and prevalence for countries without registry or published epidemiological data. Of 171 publications identified in the SLR, 10 records met the criteria for data extraction, and two records were included in the final incidence-to-prevalence model. In 2018, an estimated 74,000 AL amyloidosis cases worldwide were diagnosed during the preceding 20 years. The estimated incidence and 20-year prevalence rates were 10 and 51 cases per million population, respectively. Orphan medicinal product designation criteria of the European Medicines Agency or Electronic Code of Federal Regulations indicate that a disease must not affect > 5 in 10,000 people across the European Union or affect < 200,000 people in the US. This study provides up-to-date epidemiological patterns of AL amyloidosis, which is vital for understanding the burden of the disease, increasing awareness, and to further research and treatment options.
Targeting the RAS oncogene Takashima, Asami; Faller, Douglas V
Expert opinion on therapeutic targets,
05/2013, Letnik:
17, Številka:
5
Journal Article
Recenzirano
Odprti dostop
The Ras proteins (K-Ras, N-Ras, and H-Ras) are GTPases that function as molecular switches for a variety of critical cellular activities and their function is tightly and temporally regulated in ...normal cells. Oncogenic mutations in the RAS genes, which create constitutively-active Ras proteins, can result in uncontrolled proliferation or survival in tumor cells.
The paper discusses three therapeutic approaches targeting the Ras pathway in cancer: i) Ras itself, ii) Ras downstream pathways, and iii) synthetic lethality. The most adopted approach is targeting Ras downstream signaling, and specifically the PI3K-AKT-mTOR and Raf-MEK pathways, as they are frequently major oncogenic drivers in cancers with high Ras signaling. Although direct targeting of Ras has not been successful clinically, newer approaches being investigated in preclinical studies, such as RNA interference-based and synthetic lethal approaches, promise great potential for clinical application.
The challenges of current and emerging therapeutics include the lack of "tumor specificity" and their limitation to those cancers which are "dependent" on aberrant Ras signaling for survival. While the newer approaches have the potential to overcome these limitations, they also highlight the importance of robust preclinical studies and bidirectional translational research for successful clinical development of Ras-related targeted therapies.
Despite emerging novel therapies, treating acute myeloid leukemia (AML) remains challenging. Complexities persist in designing pivotal clinical trials and establishing acceptable endpoints for AML. ...Recent FDA guidance for drug and biological products development for AML outlines considerations for trial design. The guidance defines overall survival (OS) and event-free survival (EFS) as endpoints representing clinical benefit for AML therapies without curative intent. We highlight the EFS definition, particularly the assignment of day 1 as the event date for patients with induction treatment failures (ITFs), as recommended in the guidance. Through a comprehensive simulation study, our results show that the guidance EFS definition performs adequately with high complete remission (CR) rates but may pose challenges for low CR rates. When the experimental arm CR rate is 5% or less over the control, the use of the ITF events at day 1 for EFS definition leads to a critical power decrease, hampering the ability to predict survival benefit for a moderate OS duration. We further expand upon the EFS definition with the event date at ITF period end. Our goal is to inform investigators and regulatory agencies about the implications and limitations of various EFS definitions for future pivotal trials in AML.
•We conducted a simulation assessing impact of day 1 assignment EFS event due to ITF.•Day 1 EFS event due to ITF performs reasonably well when CR rates are high.•For low CR rates, day 1 EFS event due to ITF analysis poses a challenge.•CR rates should be considered when designing a pivotal AML study with EFS endpoint.
Induction of EBV lytic-phase gene expression, combined with exposure to an antiherpes viral drug, represents a promising targeted therapeutic approach to EBV-associated lymphomas. Short-chain fatty ...acids or certain chemotherapeutics have been used to induce EBV lytic-phase gene expression in cultured cells and mouse models, but these studies generally have not translated into clinical application. The recent success of a clinical trial with the pan-histone deacetylase (pan-HDAC) inhibitor arginine butyrate and the antiherpes viral drug ganciclovir in the treatment of EBV lymphomas prompted us to investigate the potential of several HDAC inhibitors, including some new, highly potent compounds, to sensitize EBV+ human lymphoma cells to antiviral agents in vitro. Our study included short-chain fatty acids (sodium butyrate and valproic acid); hydroxamic acids (oxamflatin, Scriptaid, suberoyl anilide hydroxamic acid, panobinostat LBH589, and belinostat PXD101); the benzamide MS275; the cyclic tetrapeptide apicidin; and the recently discovered HDAC inhibitor largazole. With the exception of suberoyl anilide hydroxamic acid and PXD101, all of the other HDAC inhibitors effectively sensitized EBV+ lymphoma cells to ganciclovir. LBH589, MS275, and largazole were effective at nanomolar concentrations and were 104 to 105 times more potent than butyrate. The effectiveness and potency of these HDAC inhibitors make them potentially applicable as sensitizers to antivirals for the treatment of EBV-associated lymphomas.
Insidious cascade of converging pathways involving oxidative stress, altered lipid metabolism, and mitochondrial injury, leading to adverse ophthalmic consequences.
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Pathological ...deterioration of mitochondrial function is increasingly linked with multiple degenerative illnesses as a mediator of a wide range of neurologic and age-related chronic diseases, including those of genetic origin. Several of these diseases are rare, typically defined in the United States as an illness affecting fewer than 200,000 people in the U.S. population, or about one in 1600 individuals. Vision impairment due to mitochondrial dysfunction in the eye is a prominent feature evident in numerous primary mitochondrial diseases and is common to the pathophysiology of many of the familiar ophthalmic disorders, including age-related macular degeneration, diabetic retinopathy, glaucoma and retinopathy of prematurity — a collection of syndromes, diseases and disorders with significant unmet medical needs. Focusing on metabolic mitochondrial pathway mechanisms, including the possible roles of cuproptosis and ferroptosis in retinal mitochondrial dysfunction, we shed light on the potential of α-lipoyl-L-carnitine in treating eye diseases. α-Lipoyl-L-carnitine is a bioavailable mitochondria-targeting lipoic acid prodrug that has shown potential in protecting against retinal degeneration and photoreceptor cell loss in ophthalmic indications.
Population pharmacokinetic (PK) and exposure‐safety analyses of alisertib were performed in children enrolled in 2 clinical trials: NCT02444884 and NCT01154816. NCT02444884 was a dose‐finding study ...in children with relapsed/refractory solid malignancies (phase 1) or neuroblastomas (phase 2). Patients received oral alisertib 45 to 100 mg/m2 as powder‐in‐capsule once daily or twice daily for 7 days in 21‐day cycles. Serial blood samples were collected up to 24 hours after dosing on cycle 1, day 1. NCT01154816 was a phase 2 single‐arm study evaluating efficacy in children with relapsed/refractory solid malignancies or acute leukemias. Patients received alisertib 80 mg/m2 as enteric‐coated tablets once daily for 7 days in 21‐day cycles. Sparse PK samples were collected up to 8 hours after dosing on cycle 1, day 1. Sources of alisertib PK variability were characterized and quantified using nonlinear mixed‐effects modeling to support dosing recommendations in children and adolescents. A 2‐compartment model with oral absorption described by 3 transit compartments was developed using data from 146 patients. Apparent oral clearance and central distribution volume were correlated with body surface area across the age range of 2 to 21 years, supporting the use of body surface area–based alisertib dosing in the pediatric population. The recommended dose of 80 mg/m2 once daily enteric‐coated tablets provided similar alisertib exposures across pediatric age groups and comparable exposure to that in adults receiving 50 mg twice daily (recommended adult dose). Statistically significant relationships (P < .01) were observed between alisertib exposures and incidence of grade ≥2 stomatitis and febrile neutropenia, consistent with antiproliferative mechanism‐related toxicities.
Pevonedistat (TAK-924/MLN4924) is a novel inhibitor of NEDD8-activating enzyme (NAE) with single-agent activity in relapsed/refractory acute myeloid leukemia (AML). We performed a phase 1b study of ...pevonedistat (PEV) with azacitidine (AZA) based on synergistic activity seen preclinically. Primary objectives included safety and tolerability, and secondary objectives included pharmacokinetics (PK) and disease response. Patients ≥60 years with treatment-naive AML (unfit for standard induction therapy) received PEV 20 or 30 mg/m2 IV on days 1, 3, and 5 combined with fixed-dose AZA (75 mg/m2 IV/subcutaneously) on days 1 to 5, 8, and 9, every 28 days. The most common treatment-emergent adverse events were constipation (48%), nausea (42%), fatigue (42%), and anemia (39%). In total, 11 deaths were observed and considered unrelated to study therapy by the investigators. Transient elevations in aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were dose limiting. The recommended phase 2 dose (RP2D) of PEV in this combination is 20 mg/m2. PEV PK was not altered by the addition of AZA. Overall response rate (ORR) based on an intent-to-treat analysis was 50% (20 complete remissions CRs, 5 complete remission with incomplete peripheral count recovery, 7 partial remissions PRs), with an 8.3-month median duration of remission. In patients receiving ≥6 cycles of therapy (n = 23, 44%), ORR was 83%. In patients with TP53 mutations, the composite CR/PR rate was 80% (4/5). Two of these patients stayed on study for >10 cycles. Baseline bone marrow blast percentage or cytogenetic/molecular risk did not influence ORR. This study was registered at www.clinicaltrials.gov as #NCT01814826.
•RP2D of PEV 20 mg/m2 in PEV/AZA combo did not alter toxicity profile of AZA; dose-limiting toxicities were transiently elevated AST/ALT.•In treatment-naive older AML patients, the intent-to-treat ORR was 50%.
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